Age related degenerative changes in the eye's retina pigment epithilium (RPE), a highly pigmented epithilium underlying the retina, occur mainly in the macula area. Since the macula is the area which enables to discern small details and to read, its deterioration may bring about visual impairment and even blindness. Age related changes of varying degrees in the macula are evident in about 10% of subjects over 50 and about 25% of subjects over 75. One of the main factors responsible for age related macular degeneration (AMD) is aging of the Retinal Pigment Epithelium (RPE) at the macular area. In the intact eye, the RPE cells, through their phagocytic activity and active metabolism, constantly remove the toxic metabolites produced by the overlaying photoreceptoric retinal cells during the visual transduction process.
As a consequence of the age dependent reduction in the metabolic and pharmaceutical activity of cells of the RPE, metabolic waste products are accumulated within these cells causing a slow deterioration of the activity of the RPE cells and their death. This deterioration, and death of cells occurs mainly in the macula region, eventually causes the degradation of the overlaying retinal layer and photoreceptors with subsequent impairment of vision or even blindness.
Although AMD is the most prevalent cause of blindness in the elder population in developed countries, there is to date no effective treatment available to prevent the development of AMD or to ameliorate the condition following the onset of this disorder.
Melanotropin (alpha melanocytic stimulating hormone (.alpha.-MSH)) is an N-Acetyl-tridecapeptide hormone which is synthesized and secreted by the intermediate lobe of the pituitary gland, and is known to control skin pigmentation in many animals by stimulating melanin synthesis and movement within integumental melanocytes. Recently, melanotropin has been also reported to affect other physiological functions including: endocrine and exocrine gland activities, temperature regulation, immuno modulation and nerve regeneration. Cellular responses to melanotropin in cultured melanoma cells include elevation of c-AMP levels, increase in melanin synthesis and stimulation of cell proliferation.
Melanotropin was found to have also various effects on the eye. This hormone causes the acceleration of the regeneration of retinal visual purple both in vivo and in vitro and increases light sensitivity (Hanoka, 1953); it was also found to stimulate the melanin synthesis in the RPE of rats with inherited retinal dystrophy (Stroeva and Bibikova, 1988). In addition, this hormone was found to increase the release of retinal neurotransmitters, especially dopamine and GABA (Bauer and Ehringer, 1980). Recently it has been found that melanotropin enhances eicosanoid production by bovine RPE in organ culture without any effect on other retinal layers (Bar-Ilan et al., 1992).
Derivatives of this naturally occurring tridecapeptide in which one or more amino acids has been replaced by another are well known. Some of these derivatives are more stable than the native protein, and others, such as Nle.sup.4 D-Phe.sup.7 .alpha.-MSH were found to be more potent than the native peptide in affecting various biological phenomenon (Dayes et al., 1987). Sawyer et al. (Sawyer et al. 1990) have established the fact that only a few amino acids are sufficient to cause the full biological activity of the native protein.